EP1745573A2 - Verfahren zur herstellung von 2 -deoxy-&bgr;-l-nukleosiden - Google Patents
Verfahren zur herstellung von 2 -deoxy-&bgr;-l-nukleosidenInfo
- Publication number
- EP1745573A2 EP1745573A2 EP04722357A EP04722357A EP1745573A2 EP 1745573 A2 EP1745573 A2 EP 1745573A2 EP 04722357 A EP04722357 A EP 04722357A EP 04722357 A EP04722357 A EP 04722357A EP 1745573 A2 EP1745573 A2 EP 1745573A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- deoxyribose
- optionally protected
- optionally
- protected
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims description 164
- 239000002777 nucleoside Substances 0.000 title claims description 136
- 238000004519 manufacturing process Methods 0.000 title description 14
- CKTSBUTUHBMZGZ-CHKWXVPMSA-N 4-amino-1-[(2s,4r,5s)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 CKTSBUTUHBMZGZ-CHKWXVPMSA-N 0.000 claims abstract description 44
- -1 alkyl acetal Chemical class 0.000 claims description 158
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 123
- 238000006243 chemical reaction Methods 0.000 claims description 104
- 230000008569 process Effects 0.000 claims description 98
- 125000000217 alkyl group Chemical group 0.000 claims description 78
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 62
- 125000003545 alkoxy group Chemical group 0.000 claims description 48
- 238000005859 coupling reaction Methods 0.000 claims description 46
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 45
- 150000001875 compounds Chemical class 0.000 claims description 44
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 42
- 125000005843 halogen group Chemical group 0.000 claims description 39
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical group CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 38
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 claims description 38
- 125000002252 acyl group Chemical group 0.000 claims description 38
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 37
- 239000002253 acid Substances 0.000 claims description 36
- 239000001257 hydrogen Substances 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 36
- 238000002360 preparation method Methods 0.000 claims description 36
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 35
- 229940045145 uridine Drugs 0.000 claims description 33
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 claims description 30
- 150000002431 hydrogen Chemical group 0.000 claims description 29
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 27
- 229940035893 uracil Drugs 0.000 claims description 25
- 150000001413 amino acids Chemical class 0.000 claims description 24
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 23
- 230000008878 coupling Effects 0.000 claims description 23
- 238000010168 coupling process Methods 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 150000002367 halogens Chemical group 0.000 claims description 22
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 20
- 125000000539 amino acid group Chemical group 0.000 claims description 20
- 150000003461 sulfonyl halides Chemical class 0.000 claims description 20
- 125000003342 alkenyl group Chemical group 0.000 claims description 19
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 claims description 19
- IQFYYKKMVGJFEH-CSMHCCOUSA-N telbivudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 IQFYYKKMVGJFEH-CSMHCCOUSA-N 0.000 claims description 19
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 claims description 19
- 125000000304 alkynyl group Chemical group 0.000 claims description 18
- 229910052794 bromium Inorganic materials 0.000 claims description 18
- 238000000605 extraction Methods 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- 150000004820 halides Chemical class 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 229940113082 thymine Drugs 0.000 claims description 15
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 claims description 14
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 claims description 14
- 238000011065 in-situ storage Methods 0.000 claims description 13
- 229910052740 iodine Inorganic materials 0.000 claims description 13
- 125000004423 acyloxy group Chemical group 0.000 claims description 12
- 238000000926 separation method Methods 0.000 claims description 12
- 150000001266 acyl halides Chemical class 0.000 claims description 11
- 150000001412 amines Chemical group 0.000 claims description 11
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 claims description 11
- 125000004001 thioalkyl group Chemical group 0.000 claims description 11
- 125000005425 toluyl group Chemical group 0.000 claims description 10
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical group CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 9
- 239000012346 acetyl chloride Substances 0.000 claims description 9
- 229910021529 ammonia Inorganic materials 0.000 claims description 9
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 9
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 9
- 230000003213 activating effect Effects 0.000 claims description 8
- 150000002243 furanoses Chemical class 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 8
- 239000001226 triphosphate Substances 0.000 claims description 8
- 235000011178 triphosphate Nutrition 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 229950003188 isovaleryl diethylamide Drugs 0.000 claims description 7
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 claims description 6
- 239000001177 diphosphate Substances 0.000 claims description 5
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims description 5
- 235000011180 diphosphates Nutrition 0.000 claims description 5
- 150000004712 monophosphates Chemical class 0.000 claims description 5
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 5
- 150000003973 alkyl amines Chemical group 0.000 claims description 4
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 4
- 125000005429 oxyalkyl group Chemical group 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 125000005140 aralkylsulfonyl group Chemical group 0.000 claims description 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 3
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 3
- 229940002612 prodrug Drugs 0.000 abstract description 72
- 239000000651 prodrug Substances 0.000 abstract description 72
- 230000015572 biosynthetic process Effects 0.000 abstract description 36
- 238000003786 synthesis reaction Methods 0.000 abstract description 36
- 229960005311 telbivudine Drugs 0.000 abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 114
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 104
- 239000000243 solution Substances 0.000 description 60
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
- 150000003833 nucleoside derivatives Chemical class 0.000 description 50
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 49
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
- 239000002904 solvent Substances 0.000 description 42
- 239000000047 product Substances 0.000 description 37
- 239000002585 base Substances 0.000 description 35
- 235000019439 ethyl acetate Nutrition 0.000 description 35
- 239000000203 mixture Substances 0.000 description 35
- 229930182470 glycoside Natural products 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
- 239000011541 reaction mixture Substances 0.000 description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 29
- 239000000543 intermediate Substances 0.000 description 29
- 229940024606 amino acid Drugs 0.000 description 25
- 235000001014 amino acid Nutrition 0.000 description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 23
- 239000003153 chemical reaction reagent Substances 0.000 description 23
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 23
- 150000003839 salts Chemical class 0.000 description 23
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 22
- 230000000670 limiting effect Effects 0.000 description 22
- 125000003835 nucleoside group Chemical group 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 229910052786 argon Inorganic materials 0.000 description 21
- 235000019441 ethanol Nutrition 0.000 description 21
- 229910001868 water Inorganic materials 0.000 description 21
- 238000007792 addition Methods 0.000 description 20
- 125000006239 protecting group Chemical group 0.000 description 20
- CKTSBUTUHBMZGZ-UHFFFAOYSA-N Deoxycytidine Natural products O=C1N=C(N)C=CN1C1OC(CO)C(O)C1 CKTSBUTUHBMZGZ-UHFFFAOYSA-N 0.000 description 19
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 19
- 238000011282 treatment Methods 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Natural products NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 18
- 238000000354 decomposition reaction Methods 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
- 238000004809 thin layer chromatography Methods 0.000 description 17
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 16
- 239000006227 byproduct Substances 0.000 description 15
- 239000003795 chemical substances by application Substances 0.000 description 15
- 229940104302 cytosine Drugs 0.000 description 15
- 125000001072 heteroaryl group Chemical group 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 238000005576 amination reaction Methods 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 238000006467 substitution reaction Methods 0.000 description 14
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 13
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- 239000000460 chlorine Substances 0.000 description 13
- 229910052801 chlorine Inorganic materials 0.000 description 13
- 125000000623 heterocyclic group Chemical group 0.000 description 13
- 239000003960 organic solvent Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 12
- 239000003054 catalyst Substances 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- 239000011737 fluorine Substances 0.000 description 12
- 229910052731 fluorine Inorganic materials 0.000 description 12
- 239000002516 radical scavenger Substances 0.000 description 12
- 239000007858 starting material Substances 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 11
- 230000000840 anti-viral effect Effects 0.000 description 11
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 10
- 125000003277 amino group Chemical group 0.000 description 10
- 239000000010 aprotic solvent Substances 0.000 description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 10
- 238000010511 deprotection reaction Methods 0.000 description 10
- 208000002672 hepatitis B Diseases 0.000 description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- 239000012535 impurity Substances 0.000 description 10
- 229940127073 nucleoside analogue Drugs 0.000 description 10
- 239000003814 drug Substances 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 125000001188 haloalkyl group Chemical group 0.000 description 9
- 230000001737 promoting effect Effects 0.000 description 9
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 8
- 150000001241 acetals Chemical class 0.000 description 8
- 230000008901 benefit Effects 0.000 description 8
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 8
- 239000007810 chemical reaction solvent Substances 0.000 description 8
- 125000001309 chloro group Chemical group Cl* 0.000 description 8
- 238000004821 distillation Methods 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000003444 phase transfer catalyst Substances 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
- 150000003573 thiols Chemical group 0.000 description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 7
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 7
- 150000001718 carbodiimides Chemical class 0.000 description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
- 238000002955 isolation Methods 0.000 description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- 238000007070 tosylation reaction Methods 0.000 description 7
- 229940086542 triethylamine Drugs 0.000 description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 6
- 125000003710 aryl alkyl group Chemical group 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 239000005549 deoxyribonucleoside Substances 0.000 description 6
- 150000004887 dithianes Chemical class 0.000 description 6
- 239000011630 iodine Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 230000000707 stereoselective effect Effects 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 6
- 238000005866 tritylation reaction Methods 0.000 description 6
- ASJSAQIRZKANQN-UHNVWZDZSA-N 2-deoxy-L-arabinose Chemical compound OC[C@H](O)[C@H](O)CC=O ASJSAQIRZKANQN-UHNVWZDZSA-N 0.000 description 5
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical group OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 5
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 5
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 5
- MXHRCPNRJAMMIM-UHFFFAOYSA-N desoxyuridine Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-UHFFFAOYSA-N 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 150000002338 glycosides Chemical class 0.000 description 5
- 229940029575 guanosine Drugs 0.000 description 5
- 150000002373 hemiacetals Chemical class 0.000 description 5
- 208000006454 hepatitis Diseases 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
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- 239000003643 water by type Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
- C07H3/02—Monosaccharides
Definitions
- This invention relates to processes for the production of 2'-deoxynucleosides and their 3'-O-acyl prodrugs, such as their 3'-O-L-aminoacyl and 3',5'-O-L-diaminoacyl prodrugs, useful in the formulation of pharmaceuticals, and in particular for pharmaceuticals for the treatment and/or prevention of viral infections such as hepatitis B virus infection.
- 3'-O-L-aminoacyl and 3',5'-O-L-diaminoacyl prodrugs useful in the formulation of pharmaceuticals, and in particular for pharmaceuticals for the treatment and/or prevention of viral infections such as hepatitis B virus infection.
- the present invention relates to processes for the production of at least an optionally protected l-halo-2-deoxyribose, ⁇ -L-thymidine, ⁇ -L- 2'-deoxyuridine, ⁇ -L-2'-deoxycytidine, 3'-O-L-valyl-2'-deoxy- ⁇ -L-cytidine, and 3 ',5'- O-L-divalyl-2'-deoxy- ⁇ -L-cytidine from stable starting materials.
- HBN is second only to tobacco as a cause of human cancer.
- the mechanism by which HBV induces cancer is unknown, although it is postulated that it may directly trigger tumor development, or indirectly trigger tumor development through chronic inflammation, cirrhosis, and cell regeneration associated with the infection.
- Hepatitis B virus has reached epidemic levels worldwide. After a two to six month incubation period in which the host is unaware of the infection, HBV infection can lead to acute hepatitis and liver damage, that causes abdominal pain, jaundice, and elevated blood levels of certain enzymes. HBN can cause fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which massive sections of the liver are destroyed. Patients typically recover from acute hepatitis. In some patients, however, high levels of viral antigen persist in the blood for an extended, or indefinite, period, causing a chronic infection. Chronic infections can lead to chronic persistent hepatitis. Patients infected with chronic persistent HBN are most common in developing countries. By mid- 1991, there were approximately 225 million chronic carriers of HBV in Asia alone, and worldwide, almost 300 million carriers. Chronic persistent hepatitis can cause fatigue, cirrhosis of the liver, and hepatocellular carcinoma, a primary liver cancer.
- Adefovir (9- ⁇ 2-(phosphonomethoxy)ethyl ⁇ adenine, also referred to as PMEA or
- L-FDDC (5-fluoro-3'-thia-2',3'-dideoxycytidine) for the treatment of hepatitis B virus in WO 92/18517.
- WO96/13512 filed by Genencor International, Inc., and Lipitek, Inc., discloses the preparation of L-ribofuranosyl nucleosides as antitumor agents and virucides.
- WO95/32984 discloses lipid esters of nucleoside monophosphates as imniuno- suppresive drugs .
- DE 4224737 discloses cytosine nucleosides and their pharmaceutical uses.
- Idenix Pharmaceuticals, Ltd. discloses 2'-deoxy--L-erythropentofurano- nucleosides, and their use in the treatment of HBV in US Patent Nos. 6,395,716; 6,444,652; 6,566,344 and 6,539,837. See also WO 00/09531.
- a method for the treatment of hepatitis B infection in humans and other host animals includes administering an effective amount of a biologically active 2'-deoxy- ⁇ -L- erythro-pentofuranonucleoside (alternatively referred to as ⁇ -L-dN or a ⁇ -L-2'-dN) or a pharmaceutically acceptable salt, ester or prodrug thereof, including ⁇ -L- deoxyribothymidine ( ⁇ -L-dT), ⁇ -L-deoxyribocytidine ( ⁇ -L-dC), ⁇ -L-deoxyribouridine ( ⁇ -L-dU), ⁇ -L-deoxyribo-guanosine ( ⁇ -L-dG), ⁇ -L-deoxyriboadenosine ( ⁇ -L-dA) and ⁇ -
- L-deoxyriboinosine ( ⁇ -L-dl), administered either alone or in combination, optionally in a pharmaceutically acceptable carrier.
- 5' and N ⁇ (cytidine) or N ⁇ (adenosine) acylated or alkylated derivatives of the active compound, or the 5'-phospholipid or 5 '-ether lipids were also disclosed.
- the 5'- triphosphates of 3'-deoxy-3'-fluoro- ⁇ -L-thymidine ( ⁇ -L-FTTP), 2',3'-dideoxy-3'-fluoro- ⁇ -L-cytidine ( ⁇ -L-FdCTP), and 2',3'-dideoxy-3'-fluoro- ⁇ -L-5-methylcytidine ( ⁇ -L- FMethCTP) were disclosed as effective inhibitors of HBV DNA polymerases.
- ⁇ -L-FTTP 3'-deoxy-3'-fluoro- ⁇ -L-thymidine
- ⁇ -FdCTP 2',3'-dideoxy-3'-fluoro- ⁇ -L-cytidine
- ⁇ -L- FMethCTP 2',3'-dideoxy-3'-fluoro- ⁇ -L-5-methylcytidine
- European Patent Application No. 0 352 248 Al to Johansson et al. discloses the use of L-ribofuranosyl compounds for the treatment of hepatitis B .
- Verri et al. disclose the use of 2'-deoxy- ⁇ -L-erythro-pentofuranonucleosides as antineoplastic agents and as anti-herpetic agents (Mol. Pharmacol. (1997), 51(1), 132- 138 and Biochem. J. (1997), 328(1), 317-20).
- Saneyoshi et al. demonstrate the use of 2'- deoxy-L-ribonucleosides as reverse transcriptase (I) inhibitors for the control of retroviruses and for the treatment of AIDS, Jpn. Kokai Tokkyo Koho JP06293645
- cytosine derivatives are useful as intermediates for production of drugs such as cytidine diphosphate choline whose generic name is Citicoline.
- Such therapeutic L-deoxynucleosides can be prepared by any number of routes.
- the deoxyribose must be activated with a good leaving group at C-l. Further, this leaving group must have the ⁇ configuration. This configuration must remain stable throughout the reaction and, in addition, the formation of the N-glycosidic bond with displacement of the leaving group must occur with inversion of the configuration thus leading to the desired ⁇ nucleoside. If these conditions are not met, the resulting product is usually a mixture of ⁇ and ⁇ nucleosides from which it is almost impossible to separate the isomers with methods other than chromatographic.
- the diphosphate can be prepared according to the procedure of Davisson et al., J. Org. Chem., 52(9), 1794-1801 (1987).
- the triphosphate can be prepared according to the procedure of Hoard et al., J. Am. Chem. Soc, 87(8), 1785-1788 (1965).
- Lawesson's reagent was added to a solution of l-(3,5-di-O-benzoyl-2-deoxy- ⁇ -L- er ⁇ t ⁇ ro-pentofuranosyl)uracil in anhydrous 1,2-dichloroethane and the reaction mixture was stirred under reflux for 2h. The solvent was then evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the 4-thio intermediate as a yellow foam.
- GDR Pat. No. 140,254 Official Gazette (1980) discloses a procedure where a uridine derivative with protected hydroxyl groups is allowed to react with an organic sulfonylating agent in the presence of sodium hydride to give a 4-O-sulfonyluridine derivative which is then aminated at the position 4 by ammonia, and deprotected, to give cytidine derivatives.
- Pharmaceutically active compounds are sometimes administered in an esterified prodrug form.
- Carboxylic acid esters are used most commonly, while phosphonate and phosphate esters are used less frequently because they fail to hydrolyze in vivo and may produce toxic byproducts (see U.S. 6,312,662 to Erion et al.).
- Acyloxyalkyl esters are sometimes used as prodrugs for phosphate and phosphonate compounds, as are cyclic phosphonate esters and aryl esters, especially phenyl and benzyl esters (Farquhar et al., J. Pharm. Sci., (1983), 72(3):324; U.S. 6,312,662 to Erion et al.).
- phosphonic acids such as, for example, phosphonoformic acid and PMEA (Adefovir; 9- (2-phosphonylmethoxy-ethyi)adenine) show antiviral activity as do carboxylic acid or ether lipid prodrugs of nucleosides (U.S. 6,458,773 to Gosselin et al.).
- Nucleoside prodrugs have been previously described for the treatment of other forms of hepatitis.
- WO 01/96353 (filed June 15, 2001) to Indenix Pharmaceuticals, Ltd. discloses 3'-prodrugs of 2'-deoxy- ⁇ -L-nucleosides for the treatment of HBV.
- Valacyclovir is in fact the L-valine ester prodrug of acyclovir (MERCK INDEX 12TH EDITION, NUMBER 10039, P10044). Historically, prodrug syntheses and formulations have typically involved the 5'- position of a nucleoside or nucleoside analogue.
- Matulic-Adamic et al. (U.S. 6,248,878) reported the synthesis of nucleoside analogues that comprise a ribofuranose ring with a phosphorus-containing group attached to the 3 '-position via an oxygen atom and a substituted pyrimidine base.
- the phosphorus-containing group includes dithioates or phosphoramidites, or may be part of an oligonucleotide. These compounds are prodrugs because they are reacted further to provide final, desired nucleosides and nucleoside analogues.
- the compounds are synthesized in a multi-step process that couples, as starting materials, a ribofuranose having an hydroxy or acetoxy group at C-l and benzoyl-protecting groups at C-2-, C-3 and C-5, and a 4-OSiMe 3 pyrimidine to produce an l-(2,3,5-tri-O-benzoyl-ribo- furanosyl)-pyrimidin-4-one; then adds ammonia in methanol to the product of the first reaction in order to remove the benzoyl protecting groups; then reacts DMT-Cl/Pyr reacted with the unprotected product compound, which results in the addition of DMT to the 5'-O position of ribofuranose; then reacts TBDMS-Cl, AgNO 3 , and Pyr/THF with the 5'-O-DMT substituted ribofuranose; and finally performs standard phosphitylation to produce the phosphorus-containing group located at the 3'-O.
- McCormick et al. described the carbonate formation at the 3' -OH of guanosine, using an unprotected ribose as a starting material (McCormick et al., J Am. Chem. Soc. 1999, 121(24):5661-5). McCormick was able to synthesize the compound by a sequential, stepwise introduction of the O- and N-glycosidic linkages, application of certain protecting groups, sulfonation and final deprotection. As one step in their process, McCormick et al. reacted unprotected guanosine with BOC-anhydride, DMAP, Et 3 ⁇ , and DMSO at room temperature for 4 hours to obtain directly a carbonate at the 3'- OH of guanosine.
- Tang et al. disclosed a process for preparing phosphoramidite prodrugs of 2'-C- ⁇ -methyl-cytidine ribonucleosides (Tang et al., J Org. Chem., 1999,
- branched nucleoside was then coupled with a suitable acyl donor, such as an acyl chloride and/or an acyl anhydride or an activated acid, in an appropriate protic or aprotic solvent and at a suitable reaction temperature, to provide the 2' or 3' prodrug of a 1', 2', 3' or 4' branched ⁇ -D or ⁇ -L nucleoside, optionally in the presence of a suitable coupling agent (see Synthetic Communications, 1978, 8(5): 327-33; J. Am. Chem. Soc,
- Possible coupling reagents are any reagents that enable compounds or moieties to be linked to one another including, but not limited to, various carbodiimides, CDI, BOP and carbonyldumidazole.
- the nucleoside preferably was not protected, but was coupled directly to an alkanoic or amino acid residue via a carbodiimide- coupling reagent.
- ⁇ -L-2'-deoxynucleosides such as ⁇ -L-thymidine, ⁇ -L-2'-deoxyuridine, and ⁇ -L-2'-deoxycytidine
- their derivatives such as the 3'-O-acyl or 3',5'-O-diacyl prodrugs, including the 3'-O-L-aminoacyl and
- 3',5'-O-L-diaminoacyl prodrugs and particularly the 3'-O-L-valinyl and 3',5'-O-L- divalinyl prodrugs.
- ⁇ -L-2'-deoxycytidine and its derivatives such as its 3'-O-acyl or 3',5'-O-diacyl prodrugs, including the 3'-O-L- aminoacyl and 3',5'-O-L-diaminoacyl prodrugs, and particularly the 3'-O-L-valinyl and
- ⁇ -L-2'- deoxycytidine and its derivatives such as its 3'-O-acyl or 3',5'-O-diacyl prodrugs, including the 3'-O-L-aminoacyl and 3',5'-O-L-diaminoacyl prodrugs, and particularly the 3'-O-L-valinyl and 3',5'-O-L-divalinyl prodrugs.
- ⁇ -L-2'-deoxycytidine and its derivatives such as its 3'-O-acyl or 3',5'-O-diacyl prodrugs, including the 3'-O-L- aminoacyl and 3',5'-O-L-diaminoacyl prodrugs, and particularly the 3'-O-L-valinyl and 3',5'-O-L-divalinyl prodrugs, from ⁇ -L-2'-deoxyuridine under mild conditions.
- the present invention is directed to an efficient synthetic route to an optionally protected l-halo-2-deoxyribose, preferably formed in such a condition that it can be stored and/or shipped.
- This process includes formation of an alkyl acetal, such as a methyl acetal, of a furanose, such as 2-deoxyribose, optionally followed by protection of the remaining hydroxyl groups, for example in the form of aromatic esters.
- the optionally protected acetal is then converted under mild conditions to a 1-halo-furanose, such as a l-halo-2- deoxyribose (halo sugar).
- the conditions involve the use of anhydrous acid halide, such as HC1, produced in situ by the reaction of an acyl halide, such as an acyl chloride, and in particular acetyl chloride, with sub-equivalent amounts of an alcohol, such as methanol.
- the substitute reaction is accomplished under anhydrous conditions.
- the stereoselective substitution of the alkyoxyl group, such as a methoxyl group, for halide, such as chloride is complete.
- the product crystallizes readily as it forms, thus avoiding the usual decomposition observed with other methods.
- 2-deoxyribose is reacted with methanol to form the 1 -methyl acetal of 2-deoxyribose, followed by protection of the 3- and 5-hydroxyl groups in the form of aromatic esters.
- the protected acetal is then converted under mild conditions to the l-chloro-2-deoxyribose derivative (chloro sugar).
- the conditions involve the use of anhydrous HC1 produced in situ by the reaction of an acetyl chloride with sub equivalent amounts of methanol.
- the substitute reaction is accomplished under anhydrous conditions. Under the conditions of the reaction, the stereoselective substitution of the methoxyl group for chloride is complete.
- the product crystallizes readily as it forms, thus avoiding the usual decomposition observed with other methods.
- the yields are usually high (such as greater than 80% from 2- deoxyribose), the product is stable and usually has a very high content of the active intermediate (for example greater than 97%, as evaluated by a HPLC procedure or an argentometric method).
- a preferred embodiment of the halo sugar production process includes a series of steps to convert the 1 -hydroxyl group of 2-deoxyribose to a halo group.
- the starting material 2-deoxyribose (a hemiacetal) is first transformed to 1- O-alkyl-2-deoxyribose (an acetal) through acid catalyzed alcoholic conversion of the hemiacetal group to the acetal or 2'-deoxy ribose alkyl glycoside.
- the alkyl group of the alkyl glycoside is methyl or ethyl, preferably methyl.
- the hydroxyls of the 2-deoxyribose alkyl glycoside are then optionally protected by conversion to esters.
- the alkyl glycoside is reacted with an aromatic acid halide and acid scavenger to form the 3,5-di-O-diarylacyl-2-deoxyribose alkyl glycoside.
- a preferred arylacyl group is a toluoyl group corresponding to the aromatic acid toluic acid.
- the remaining step of the halo sugar production involves a substitution reaction of the alkoxy acetal group.
- the alkoxy group of the 3,5-O-diarylacyl-2- deoxyribose alkyl glycoside undergoes a substitution reaction with halide to form the 1- halo-3,5-O-diarylacyl-2-deoxyribose, preferably under anhydrous conditions.
- the coupling reaction was found to be dependent on the solvent and the ratio of silylated base to chloro-sugar.
- the solvent requirement can be very strict.
- chloroform provides good yields with high stereoselectivity.
- An excess of silylated base promotes the formation of the ⁇ nucleoside in greater proportion. While a 1:1 ratio can lead to a ⁇ / ⁇ of ca 10-12, a molar excess, such as a 2 molar excess, of the silylated base can provide ratios as high as 40-45.
- the excess base after decomposition, is easily removed with the help of a filtering aid. Further, the ⁇ isomer is easily removed by selective crystallization, for example from 95% ethyl alcohol.
- the protected pure ⁇ nucleosides thus isolated are then subjected to a sodium methoxide catalyzed trans esterification reaction in methanol.
- the free nucleosides are easily crystallized in almost quantitative yields. In this manner L-dT and LdU may be easily made in large quantities.
- This invention also discloses an efficient synthetic route to cytidine nucleosides, such as L-2'-deoxycytidine (L-dC), from available precursors with the option of introducing functionality as needed.
- L-dC L-2'-deoxycytidine
- the process of synthesis is applicable to a wide range of derivatives of cytidine.
- the L-dC compounds made according to the present invention can also be used as synthetic intermediates for the preparation of a large variety of other nucleoside analogs, including, but not limited to, 2',3'-dideoxy and other derivatives obtained by subsequent functional group manipulations.
- This process utilizes a sulfonyl halide, such as tosyl chloride, optionally in the presence of a phase transfer catalyst, such as a pyridinium salt, to achieve the subsequent amination, for example with gaseous or liquid ammonia, of ⁇ -(D or L)- or -(D or L)- uridine, such as ⁇ -L-2'-deoxyuridine, to produce a ⁇ -(D or L)- or ⁇ -(D or L)-cytidine 5 such as a ⁇ -L-dC.
- a phase transfer catalyst such as a pyridinium salt
- the amination sequence is initiated with the selective blocking of the 5'-OH, for example with BOC.
- the activation of the uracil moiety is achieved under very mild conditions by reacting the optionally protected derivative, for example the di-BOC derivative, with a sulfonyl halide, such as tosyl chloride, followed by addition of liquid (or gaseous) ammonia and allowing the mixture to react at room temperature.
- the ammonolysis is regioselective leading to mixtures of the uracil and cytosine nucleosides in a ratio of ca. 1:12.
- the present invention is also directed to an efficient non-chromatographic separation of residual uridine derivatives from cytidine derivatives, wherein the substituents R 1 through R 5 may be almost any organic group.
- This separation process is scalable to multi-kilo preparations. The process takes advantage of the basicity of cytidine derivatives to form relatively water- soluble salts with hydrochloric acid and the selective extraction of the non basic components of the reaction mixture. In one embodiment of the invention, the recovery of the required blocked cytosine nucleoside is quantitative.
- the method for preparing ⁇ -(D or L)- or ⁇ -(D or L)-cytidine includes the following:
- R 1 is a hydrogen atom, an alkyl group, a substituted alkyl group, a halogen atom, an alkoxyl group or a substituted alkoxy group
- the alkyl groups for R 1 include lower alkyl groups with 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl and gemdimethyl butyl (i.e., 6 carbons) of all isomeric forms
- the halogen includes fluorine and chlorine
- the alkoxyl groups include lower alkoxyl groups with 1 to 6 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy
- the alkyl and alkoxyl groups may be substituted with a hydroxyl group, an amino group or a halogen atom such as fluorine, chlorine, bromine, and iodine;
- each R and R is independently hydrogen, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO- substituted aryl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate derivative, wherein in certain embodiments, each of the alkyl groups may be from 1 to 6 carbons; each of the alkoxyalkyl groups may be from 2 to 10 carbons; each of the aryloxyalkyl groups may be from 7 to 15 carbons; each of the aryl groups may be from 6 to 18 carbons; each of the arylalkyl groups may be from 7 to 15 carbons; each of the amino acid residues may be any of the naturally occurring alpha amino acids and in addition, non-naturally occurring amino acids such as taurine, beta amino propionic acid or
- each R 4 and R 5 is independently a hydrogen atom, an alkyl group, a substituted alkyl group, a halogen atom, an alkoxyl group, a substituted alkoxyl group, or an acyloxyl group, wherein in certain embodiments, the alkyl groups referred to in the definition of R 4 and/or R 5 include lower alkyl groups with 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and gem-dimethyl butyl; the halogen includes fluorine, bromine and chlorine; the alkoxyl groups include lower alkoxyl groups with 1 to 6 carbon atoms such as methoxy, ethoxy, n-propoxy, and n- epoxy; the acyloxy groups include O-carboxy aliphatic or aromatic groups, such as acetyl, benzoyl, toluoyl, p-Cl-benzoyl; and
- phase transfer catalyst such as a pyridinium salt of structure (III)
- X is a halogen (F, CI, Br, and I);
- R , R and R are independently hydrogen, alkyl, alkenyl or alkynyl, though preferably a lower alkyl;
- Y 1 , Y 2 , Y 3 and Y 4 are independently hydrogen, halogen, alkyl, alkenyl or alkynyl, acyl, alkoxy or thioalkyl, though preferably hydrogen; and then
- R , ⁇ , R , R , R , and R are defined above.
- the method is directed to the preparation of a ⁇ -L-2'-deoxy- cytidine, which includes the following:
- R and R are independently hydrogen, acyl, silyl or a derivative of an amino acid; and R 1 is hydrogen, halogen, alkyl, alkenyl or alkynyl, acyl, amine, alkylamine, aminoalkyl, hydroxyl, alkoxy, oxyalkyl, thiol, thioalkyl or alkylmercaptan; and then
- phase transfer catalyst such as a pyridinium salt of structure (III)
- X is a halogen (F, CI, Br, and I);
- R 11 , R 12 and R 13 are independently hydrogen, alkyl, alkenyl or alkynyl, though preferably a lower alkyl;
- Y 1 , Y 2 , Y 3 and Y 4 are independently hydrogen, halogen, alkyl, alkenyl or alkynyl, acyl, alkoxy or thioalkyl, though preferably hydrogen; and then c) reacting the activated compound with an amine, such as gaseous or liquid ammonia, to form a ⁇ -L-2'-deoxy-cytidine of structure (IV*)
- the process further includes esterifing the nucleosides, such as 2'-deoxy- ⁇ -L-nucleosides, to obtain the corresponding 5', 3', and/or 3',5'-prodrugs, such as the 5'-aminoacyl, 3'-aminoacyl, and/or 3',5'-diaminoacyl prodrugs, and in particular 5'-L-valinyl, 3'-L-valinyl, and/or 3',5'-L-divalinyl prodrugs, and specifically 5 ' -L-valinyl, 3 ' -L-valinyl, and/or 3 ' ,5 ' -L-divalinyl prodrugs of L-dT and
- this additional process steps includes the following steps:
- B is a pyrimidine, purine, heterocyclic or heteroaromatic base, optionally protected
- each R 4 and R 5 is independently a hydrogen atom, an alkyl group, a substituted alkyl group, a halogen atom, an alkoxyl group, a substituted alkoxyl group, or an acyloxyl group, wherein in certain embodiments, the alkyl groups referred to in the definition of R 4 and/or R 5 include lower alkyl groups with 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and gem-dimethyl butyl; the halogen includes fluorine, bromine and chlorine; the alkoxyl groups include lower alkoxyl groups with 1 to 6 carbon atoms such as methoxy, ethoxy, n-propoxy, and n- epoxy; the acyloxy groups include O-carboxy aliphatic or aromatic groups, such as acetyl, benzoyl, toluoyl, p-Cl-benzoyl; and
- R 2 and R 3 are independently hydrogen, acyl, silyl or a derivative of an amino acid; and at least one of R and R are a derivative of an amino acid.
- this additional process steps includes the following steps:
- B is a pyrimidine, purine, heterocyclic or heteroaromatic base, optionally protected
- R and R are independently hydrogen, acyl, silyl or a derivative of an amino acid; and at least one of R and R are a derivative of an amino acid.
- only the 3 '-hydroxyl is esterified.
- introduction of the acyl moiety, such as a valyl moiety, at 3 '-hydroxyl is accomplished by preliminary selective blocking of 5' -OH. This is easily achieved with the use of trityl chloride under controlled conditions.
- the intermediate thus formed is selectively de-tritylated under conditions that keep the t-butyl-oxy-carbonyl (BOC) protecting group of the valyl moiety intact.
- BOC t-butyl-oxy-carbonyl
- the present invention includes a process for the synthesis of 3'-prodrugs or 3 ',5 '-prodrugs of L-dC, for example 3'-O-acyl or 3',5'-diacyl prodrugs of L-dC, such as 3'-O-aminoacyl or 3',5'-O-diaminoacyl prodrugs of LdC, and in particular 3'-O-L-valinyl or 3',5'-O-L-divalinyl prodrugs of L-dC, wherein the 3' and/or 5'- hydroxyl is esterified prior to amination of the optionally protected 2'-deoxyuridine.
- 3'-prodrugs or 3 ',5 '-prodrugs of L-dC for example 3'-O-acyl or 3',5'-diacyl prodrugs of L-dC, such as 3'-O-aminoacyl or 3',5'-O-dia
- the invention is directed to a process of the synthesis of 3'- prodrugs or 3 ',5 '-prodrugs of L-dC, for example 3'-O-acyl or 3',5'-diacyl prodrugs of L- dC, such as 3'-O-aminoacyl or 3',5'-O-diaminoacyl prodrugs of LdC, and in particular 3'-O-L-valinyl or 3',5 5 -O-L-divalinyl prodrugs of L-dC, wherein the 3' and/or 5'- hydroxyl is esterified to the desired bio-labile substituent subsequent to the amination of the optionally protected 2 9 -deoxyuridine.
- the synthesis can follow the following scheme:
- the present invention also reveals five compounds that constitute intermediates in the synthetic routes to final cytidine compounds. These compounds include:
- the invention of a mild and robust procedure to produce large quantities of a stable activated 2-deoxy-sugar capable of giving highly stereoselective coupling reactions that lead to ⁇ 2'-deoxy-nucleosides.
- Figure 1 is a non-limiting illustrative example according to the present invention of the synthesis of 4-(NN-dimethylamino)pyridinium 4-toluenesulfonate from DMAP and TsOH.
- Figure 2 is a non-limiting illustrative example according to the present invention of the synthesis of 3',5'-di-(N-Boc-L-valinyl)-2'-deoxy- ⁇ -L-cytidine from 3',5'-di-(N- Boc-L-valinyl)-2'-deoxy- ⁇ -L-uridine.
- Figure 3 is an illustrative scheme according to the present invention depicting the conversion of 2 '-deoxyribose to l'-chloro-2'-deoxyribose and the coupling of this compound with a silyled thymine to give, after deprotection, ⁇ -L-thymine.
- Figure 4 is a non-limiting illustrative scheme according to the present invention, depicting the conversion of L-dU to Nal-L-dC dihydrochloride.
- the present invention is directed to an efficient synthetic route to an optionally protected l-halo-2-deoxyribose, preferably formed in such a condition that it can be stored and/or shipped.
- This process includes formation of an alkyl acetal, such as a methyl acetal, of a furanose, such as 2-deoxyribose, optionally followed by protection of the remaining hydroxyl groups, for example in the form of aromatic esters.
- the optionally protected acetal is then converted under mild conditions to a 1-halo-furanose, such as a l-halo-2- deoxyribose (halo sugar).
- the conditions involve the use of anhydrous acid halide, such as HC1, produced in situ by the reaction of an acyl halide, such as an acyl chloride, an in particular acetyl chloride, with sub-equivalent amounts of an alcohol, such as methanol.
- the substitute reaction is accomplished under anhydrous conditions.
- the stereoselective substitution of the alkyoxyl group, such as a methoxyl group, for halide, such as chloride is complete.
- the product crystallizes readily as it forms, thus avoiding the usual decomposition observed with other methods.
- 2-deoxyribose is reacted with methanol to form the 1 -methyl acetal of 2-deoxyribose, followed by protection of the 3- and 5-hydroxyl groups in the form of aromatic esters.
- the protected acetal is then converted under mild conditions to the l-chloro-2-deoxyribose derivative (chloro sugar).
- the conditions involve the use of anhydrous HCl produced in situ by the reaction of an acetyl chloride with sub equivalent amounts of methanol.
- the substitute reaction is accomplished under anhydrous conditions. Under the conditions of the reaction, the stereoselective substitution of the methoxyl group for chloride is complete.
- the product crystallizes readily as it forms, thus avoiding the usual decomposition observed with other methods.
- the yields are usually high (such as greater than 80% from 2- deoxyribose), the product is stable and usually has a very high content of the active intermediate (such as greater than 97%, as evaluated by a HPLC procedure or an argentometric method).
- a preferred embodiment of the halo sugar production process includes a series of steps to convert the 1 -hydroxyl group of 2-deoxyribose to a halo group.
- the starting material 2-deoxyribose (a hemiacetal) is first transformed to 1- O-alkyl-2-deoxyribose (an acetal) through acid catalyzed alcoholic conversion of the hemiacetal group to the acetal or 2'-deoxy ribose alkyl glycoside.
- the alkyl group of the alkyl glycoside is methyl or ethyl, preferably methyl.
- the hydroxyls of the 2-deoxyribose alkyl glycoside are then optionally protected by conversion to esters.
- the alkyl glycoside is reacted with an aromatic acid halide and acid scavenger to form the 3,5-di-O-diarylacyl-2-deoxyribose alkyl glycoside.
- a preferred arylacyl group is a toluoyl group corresponding to the aromatic acid toluic acid.
- the remaining step of the halo sugar production involves a substitution reaction of the alkoxy acetal group.
- the alkoxy group of the 3,5-O-diarylacyl-2- deoxyribose alkyl glycoside undergoes a substitution reaction with halide to form the 1- halo-3,5-O-diarylacyl-2-deoxyribose, preferably under anhydrous conditions. .
- the coupling reaction was found to be dependent on the solvent and the ratio of silylated base to chloro-sugar.
- the solvent requirement can be strict.
- chloroform provides good yields with high stereoselectivity.
- An excess of silylated base promotes the formation of the ⁇ nucleoside in greater proportion. While a 1:1 ratio can lead to a ⁇ / of ca 10-12, a molar excess, such as a 2 molar excess, of the silylated base can provide ratios as high as 40-45.
- the excess base after decomposition, is easily removed with the help of a filtering aid. Further, the isomer is easily removed by selective crystallization, for example from 95% ethyl alcohol.
- the protected pure ⁇ nucleosides thus isolated are then subjected to a sodium n ethoxide catalyzed trans esterification reaction in methanol.
- the free nucleosides are easily crystallized in almost quantitative yields. In this manner L-dT and LdU may be easily made in large quantities.
- This invention also discloses an efficient synthetic route to cytidine nucleosides, such as L-2'-deoxycytidine (L-dC), from available precursors with the option of introducing functionality as needed.
- L-dC L-2'-deoxycytidine
- the process of synthesis is applicable to a wide range of derivatives of cytidine.
- the L-dC compounds made according to the present invention can also be used as synthetic intermediates for the preparation of a large variety of other nucleoside analogs, including, but not limited to, 2 ',3 '-dideoxy and other derivatives obtained by subsequent functional group manipulations.
- This process utilizes a sulfonyl halide, such as tosyl chloride, optionally in the presence of a phase transfer catalyst, such as a pyridinium salt, to achieve the subsequent amination, for example with gaseous or liquid ammonia, of ⁇ -(D or L)- or ⁇ -(D or L)- uridine, such as ⁇ -L-2'-deoxyuridine, to produce a ⁇ -(D or L)- or -(D or L)-cytidine, such as a ⁇ -L-dC.
- a phase transfer catalyst such as a pyridinium salt
- the amination sequence is initiated with the selective blocking of the 5'-OH, for example with BOC.
- the activation of the uracil moiety is achieved under very mild conditions by reacting the optionally protected derivative, for example the di-BOC derivative, with a sulfonyl halide, such as tosyl chloride, followed by addition of liquid (or gaseous) ammonia and allowing the mixture to react at room temperature.
- the ammonolysis is regioselective leading to mixtures of the uracil and cytosine nucleosides in a ratio of ca. 1:12.
- the present invention is also directed to an efficient non-chromatographic separation of residual uridine derivatives from cytidine derivatives, wherein the substituents R 1 through R 5 may be almost any organic group.
- This separation process is scalable to multi-kilo preparations. The process takes advantage of the basicity of cytidine derivatives to form relatively water- soluble salts with hydrochloric acid and the selective extraction of the non basic components of the reaction mixture. In one embodiment of the invention, the recovery of the required blocked cytosine nucleoside is quantitative.
- the method for preparing ⁇ -(D or L)- or ⁇ -(D or L)-cytidine includes the following:
- R 1 is a hydrogen atom, an alkyl group, a substituted alkyl group, a halogen atom, an alkoxyl group or a substituted alkoxy group
- the alkyl groups for R 1 include lower alkyl groups with 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl and gemdimethyl butyl (i.e., 6 carbons) of all isomeric forms
- the halogen includes fluorine and chlorine
- the alkoxyl groups include lower alkoxyl groups with 1 to 6 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy
- the alkyl and alkoxyl groups may be substituted with a hydroxyl group, an amino group or a halogen atom such as fluorine, chlorine, bromine, and iodine;
- each R 2 and R 3 is independently hydrogen, straight chained, branched or cyclic alkyl, CO-alkyl, CO-aryl, CO-alkoxyalkyl, CO-aryloxyalkyl, CO- substituted aryl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, amino acid residue, mono, di, or triphosphate, or a phosphate derivative, wherein in certain embodiments, each of the alkyl groups may be from 1 to 6 carbons; each of the alkoxyalkyl groups may be from 2 to 10 carbons; each of the aryloxyalkyl groups may be from 7 to 15 carbons; each of the aryl groups may be from 6 to 18 carbons; each of the arylalkyl groups may be from 7 to 15 carbons; each of the amino acid residues may be any of the naturally occurring alpha amino acids and in addition, non-naturally occurring amino acids such as taurine, beta amino propionic acid
- each R 4 and R 5 is independently a hydrogen atom, an alkyl group, a substituted alkyl group, a halogen atom, an alkoxyl group, a substituted alkoxyl group, or an acyloxyl group, wherein in certain embodiments, the alkyl groups referred to in the definition of R 4 and/or R 5 include lower alkyl groups with 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and gem-dimethyl butyl; the halogen includes fluorine, bromine and chlorine; the alkoxyl groups include lower alkoxyl groups with 1 to 6 carbon atoms such as methoxy, ethoxy, n-propoxy, and n- epoxy; the acyloxy groups include O-carboxy aliphatic or aromatic groups, such as acetyl, benzoyl, toluoyl, p-Cl-benzoyl; and
- phase transfer catalyst such as a pyridinium salt of structure (III)
- X is a halogen (F, CI, Br, and I);
- R 11 , R 12 and R 13 are independently hydrogen, alkyl, alkenyl or alkynyl, though preferably a lower alkyl;
- Y 1 , Y 2 , Y 3 and Y 4 are independently hydrogen, halogen, alkyl, alkenyl or alkynyl, acyl, alkoxy or thioalkyl, though preferably hydrogen; and then
- R 1 , R 2 , R 3 , R 4 , and R 5 are defined above.
- any of the groups of R 1 - R 5 can independently be substituted.
- Preferred embodiments for the uracil nucleoside of formula I include those wherein R 1 , R 4 , and R 5 are H; wherein R 1 is a methyl group, and R 4 , and R 5 are H; wherein R 2 is an amino acid residue, and especially
- the method is directed to the preparation of a ⁇ -L-2'-deoxy- cytidine, which includes the following:
- R 2 and R 3 are independently hydrogen, acyl, silyl or a derivative of an amino acid
- R 1 is hydrogen, halogen, alkyl, alkenyl or alkynyl, acyl, amine, alkylamine, aminoalkyl, hydroxyl, alkoxy, oxyalkyl, thiol, thioalkyl or alkylmercaptan; and then
- phase transfer catalyst such as a pyridinium salt of structure (III)
- X is a halogen (F, CI, Br, and I);
- R 11 , R 12 and R 13 are independently hydrogen, alkyl, alkenyl or alkynyl, though preferably a lower alkyl;
- Y 1 , Y 2 , Y 3 and Y 4 are independently hydrogen, halogen, alkyl, alkenyl or alkynyl, acyl, alkoxy or thioalkyl, though preferably hydrogen; and then
- the process further includes esterifing the nucleosides, such as 2'-deoxy- ⁇ -L-nucleosides, to obtain the corresponding 5', 3', and/or 3 ',5 '-prodrugs, such as the 5'-aminoacyl, 3 '-aminoacyl, and/or 3',5'-diaminoacyl prodrugs, and in particular 5'-L-valinyl, 3'-L-valinyl, and/or 3',5'-L-divalinyl prodrugs, and specifically 5'-L-valinyl, 3'-L-valinyl, and/or 3',5'-L-divalinyl prodrugs of L-dT and L-dC.
- this additional process steps includes the following steps:
- B is a pyrimidine, purine, heterocyclic or heteroaromatic base, optionally protected
- each R and R 5 is independently a hydrogen atom, an alkyl group, a substituted alkyl group, a halogen atom, an alkoxyl group, a substituted alkoxyl group, or an acyloxyl group, wherein in certain embodiments, the alkyl groups referred to in the definition of R 4 and/or R 5 include lower alkyl groups with 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and gem-dimethyl butyl; the halogen includes fluorine, bromine and chlorine; the alkoxyl groups include lower alkoxyl groups with 1 to 6 carbon atoms such as methoxy, ethoxy, n-propoxy, and n- epoxy; the acyloxy groups include O-carboxy aliphatic or aromatic groups, such as acetyl, benzoyl, toluoyl, p-Cl-benzoyl; and the
- R 2' and R 3' are independently hydrogen, acyl, silyl or a derivative of an amino acid; and at least one of R and R are a derivative of an amino acid.
- this additional process steps includes the following steps:
- B is a pyrimidine, purine, heterocyclic or heteroaromatic base, optionally protected
- R 2 and R 3 are independently hydrogen, acyl, silyl or a derivative of
- only the 3 '-hydroxyl is esterified.
- introduction of the acyl moiety, such as a valyl moiety, at 3 '-hydroxyl is accomplished by preliminary selective blocking of 5' -OH. This is easily achieved with the use of trityl chloride under controlled conditions.
- the intermediate thus formed is selectively de-tritylated under conditions that keep the t-butyl-oxy-carbonyl (BOC) protecting group of the valyl moiety intact.
- BOC t-butyl-oxy-carbonyl
- the present invention includes a process for the synthesis of 3'-prodrugs or 3 ',5 '-prodrugs of L-dC, for example 3'-O-acyl or 3',5'-diacyl prodrugs of L-dC, such as 3'-O-aminoacyl or 3',5'-O-diaminoacyl prodrugs of LdC, and in particular
- the invention is directed to a process of the synthesis of 3'- prodrugs or 3 ',5 '-prodrugs of L-dC, for example 3'-O-acyl or 3',5'-diacyl prodrugs of L- dC, such as 3 5 -O-aminoacyl or 3',5'-O-diaminoacyl prodrugs of LdC, and in particular
- the synthesis can follow the following scheme:
- the present invention also reveals five compounds that constitute intermediates in the synthetic routes to final cytidine compounds. These compounds include:
- the invention of a mild and robust procedure to produce large quantities of a stable activated 2-deoxy-sugar capable of giving highly stereoselective coupling reactions that lead to ⁇ 2'-deoxy-nucleosides.
- reaction conditions should take into account the ease of activating the L-2'-deoxyuridine with the sulfonyl halide.
- Some combinations of temperature and solvent may lead to decreased yields.
- the coupling reaction is exothermic, thus can potentially lead to side products such as anhydrides and/or ureas. Therefore, in one embodiment, to overcome these undesirable side reactions, the reaction is run at room temperature with large excess of select reagents, such as carbodiimide and valine.
- the coupling reaction is run at lower temperatures, e.g. 15 + 2 °C, to obtain almost pure product.
- the solvent systems can also be critical.
- the dioxane when the prodrug precursor, di-L-Boc-Naline-L-dC is deprotected with HCl in dioxane, the dioxane has an increased affinity to the prodrug and cannot be completely removed from the desired product, with 5-6% of the product being dioxane. If, on the other hand, ethyl acetate is employed as the solvent, the desired product has almost no trace of solvent.
- the L-dC nucleoside can then be reduced to a L-2',3'-dideoxycytidine or a L-2',3'-dideoxy-2',3'-didehydrocytidine using known methods; as a non-limiting illustrative example, Townsend, et al., Chemistry of Nucleosides and Nucleotides. Volume 1, Plenum Press: New York, teaches reduction of nucleosides at the 3' position to give 2',3'-dideoxynucleosides and elimination of the 3'-hydroxyl to give 2',3'- dideoxy-2',3'-didehydronucleosides.
- the 3 '-position can be modified to form 3' or 5' substituted cytidine derivatives, or a combination thereof, also using known chemistry to those skilled in the art.
- Kuzuhara, H., et al., U.S. Patent No. 5,144,018 (1992) teaches functionalizing the relevant hydroxyl by activation and subsequent substitution.
- the term “substantially free of or “substantially in the absence of refers to a nucleoside composition that includes at least 85 or 90% by weight, preferably 95% to 98 % by weight, and even more preferably 99% to 100% by weight, of the designated enantiomer of that nucleoside.
- the compounds are substantially free of enantiomers.
- isolated refers to a nucleoside composition that includes at least 85 or 90% by weight, preferably 95% to 98 % by weight, and even more preferably
- nucleoside 99% to 100% by weight, of the nucleoside, the remainder comprising other chemical species or enantiomers.
- alkyl refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon, including but not limited to those of Ci to C 16 , and specifically includes methyl, trifluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2- dimethylbutyl, and 2,3-dimethylbutyl.
- the alkyl group can be optionally substituted with one or more moieties such as a halo (F, CI, Br, or I, e.g. CH 2 F or CF 3 ), alkyl, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, thiol, imine, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrozine, carbamate, phosphonic acid, phosphate, phosphonate
- lower alkyl refers to a Ci to C saturated straight, branched, or if appropriate, a cyclic (for example, cyclopropyl) alkyl group, including both substituted and unsubstituted forms.
- alkylen ⁇ or alkenyl refers to a saturated hydrocarbyldiyl radical of straight or branched configuration, including but not limited to those that have from one to ten carbon atoms. Included within the scope of this term are mefhylene, 1,2-ethane- diyl, 1,1-ethane-diyl, 1,3-propane-diyl, 1,2-propane-diyl, 1,3-butane-diyl, 1,4-butane-diyl and the like.
- alkylene group or other divalent moiety disclosed herein can be optionally substituted with one or more moieties selected from the group consisting of alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrozine, carbamate, phosphonic acid, phosphonate, or any other viable functional group that does not inhibit the pharmacological activity of this compound, either un
- aryl refers to phenyl, biphenyl, or naphthyl, and preferably phenyl.
- the term includes both substituted and unsubstituted moieties.
- the aryl group can be substituted with one or more moieties selected from the group consisting of bromo, chloro, fluoro, iodo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al, Protective Groups in
- halo or halogen, as used herein, includes chloro, bromo, iodo, and fluoro.
- alkoxy refers to a moiety of the structure -O-alkyl, wherein alkyl is as defined above.
- acyl refers to a group of the formula C(O)R', wherein
- R' is an alkyl, aryl, alkaryl or aralkyl group, or substituted alkyl, aryl, aralkyl or alkaryl, wherein these groups are as defined above.
- heteroaromatic base refers to an aromatic that includes at least one sulfur, oxygen, nitrogen or phosphorus in the aromatic ring.
- heterocyclic base refers to a nonaromatic cyclic group wherein there is at least one heteroatom, such as oxygen, sulfur, nitrogen, or phosphorus in the ring.
- the heteroaromatic group can be optionally substituted as described above for aryl.
- the heterocyclic group can be optionally substituted with one or more moieties selected from the group consisting of alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrozine, carbamate, phosphonic acid, phosphonate, or any other viable functional group that does not inhibit the pharmacological activity of this compound, either unprotected, or protected as necessary
- the heteroaromatic can be partially or totally hydrogenated as desired.
- dihydropyridine can be used in place of pyridine.
- Functional oxygen and nitrogen groups on the heteroaryl group can be protected as necessary or desired.
- Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t- butyldiphenylsilyl, trityl or substituted trityl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenelsulfonyl.
- pyrimidine, purine, heteroaromatic base, or heterocyclic base includes, but is not limited to, adenine, N -alkylpurines, N -acylpurines (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N 6 -benzylpurine, N 6 -halopurine, N 6 - vinylpurine, N 6 -acetylenic purine, N 6 -acyl purine, N 6 "hydroxyalkyl purine, N 6 -thioalkyl purine, N 2 -alkylpurines, v-alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5- methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or 4- mercaptopyrmidine, uracil, 5-halouracil, including 5-fluorouracil, C -alkylpyrimidine
- Purine bases specifically include, but are not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine.
- Functional oxygen and nitrogen groups on the base can be protected as necessary or desired.
- Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimefhylsilyl and t-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.
- the pyrimidine, purine, heteroaromatic base, or heterocyclic base can optionally substituted such that it forms a viable prodrug, which can be cleaved in vivo.
- appropriate substituents include acyl moiety, an amine or cyclopropyl (e.g., 2-amino, 2,6-diamino or cyclopropyl guanosine).
- amino acid includes naturally occurring and synthetic ⁇ , ⁇ ⁇ or ⁇ amino acids, and includes but is not limited to, alanyl, valinyl, leucinyl, isoleuccinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, ⁇ - alanyl, ⁇ -valinyl, ⁇ -leucinyl, ⁇ -isoleuccinyl, ⁇ -prolinyl, ⁇ -phenylalaninyl, ⁇ - tryptophanyl, ⁇ -methioninyl, ⁇ -glycinyl, ⁇ -serinyl,
- halo-sugar such as a chloro-sugar
- first is the conversion of furanose, such as 2-deoxy ribose, that is a hemiacetal, to an alkyl acetal or alkyl glycoside, such as l-O-methyl-2-deoxy ribose; followed by the optional protection of the remaining free hydroxyls if desired, for example as ester groups (the protecting ester may be formed from an acyl group of about 3 to about 20 carbons, preferably as arylacyl group of 7 to 15 carbons, more preferably as benzoyl or substituted benzoyl groups, most preferably as toluoyl groups); third is the substitution of the alkoxy group, such as the methoxy group, with a halogen, for example a chlorine, using anhydrous acid halide, such as HCl generated in situ.
- a halogen for example a chlorine
- methanol a compound selected from the hemiacetal of the furanose, such as 2-deoxy ribose, methanol is preferred.
- the methoxy group is a good leaving group for the subsequent halo substitution reaction. While the following description may include methanol, it is understood that another alcohol, such as ethanol, may also be used.
- the conversion of the hemiacetal to the alkyl glycoside, such as methyl glycoside, is conducted under acidic conditions followed by quenching with an acid scavenger.
- the starting compound, such as 2-deoxyribose is combined with a stoichiometric excess of alcohol, such as methanol, and a catalytic amount of acid.
- Suitable catalytic acids include organic sulfonic acids such as toluene sulfonic acid and methyl sulfonic acids, and carboxylic acids, preferably organic sulfonic acids such as toluene sulfonic acid and methyl sulfonic acids.
- the reaction is monitored to completion and then the acid catalyst is quenched by addition of an acid scavenger.
- Suitable acid scavengers include any acid scavenger known in the art, including, but not limited to, triethylamine, pyridine, and dimethylaminopyridine. Isolation of the glycoside can be accomplished by removal of the excess alcohol, preferably by vacuum distillation.
- the conversion of the hemiacetal to the alkyl glycoside can be carried out at any temperature that achieves the desired results, i.e., that is suitable for the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products.
- Preferred temperatures are from room temperature to 30 °C.
- the free hydroxyls of the alkyl glycoside can optionally be protected to prevent their interaction in the following halide substitution step.
- Protecting groups include any suitable protecting group known in the art, including acyl and silyl groups.
- the protection of the free hydroxyls can be accomplished by methods well known to those skilled in the art, as taught in Greene, et al, Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.
- the glycoside of the previous step can be protected by an acyl group by dissolving the alkyl glycoside in an appropriate solvent and reacting the appropriate acyl halide, optionally in the presence of an acid scavenger.
- Suitable acid scavengers include any acid scavenger known in the art, including, but not limited to, triethylamine, pyridine, and dimethylaminopyridine.
- Solvents can consist of any aprotic solvent including, but not limiting to, alkyl solvents such as hexane and cyclohexane, toluene, acetone, ethyl acetate, dithianes, THF, dioxane, acetonitrile, dichloromefhane, dichloroethane, diethyl ether, pyridine, dimefhylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide, or any combination thereof, though preferably ethyl acetate.
- alkyl solvents such as hexane and cyclohexane, toluene, acetone, ethyl acetate, dithianes, THF, dioxane, acetonitrile, dichloromefhane, dichloroethane, diethyl ether, pyridine, dimefhylformamide (DMF), dimethyls
- This reaction can be accomplished at any temperature that allows the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products.
- the preferred temperature is room temperature.
- the course of the reaction can be followed by appropriate identification techniques.
- the acid scavenger salts can be extracted into acidic aqueous solution and the organic solution concentrated for subsequent use.
- the optionally protected glycoside of step 2) can be converted to the halo sugar, preferably the chloro sugar, by exposing the protected alkyl glycoside to a substitution reaction.
- the organic solution of protected glycoside can be combined with a stoichometric excess of an acyl halide followed by addition of the alcohol.
- the halo sugar can be prepared in any solvent that is suitable for the temperature and the solubility of the reagents.
- Solvents can consist of any aprotic solvent including, but not limiting to, alkyl solvents such as hexane and cyclohexane, toluene, acetone, ethyl acetate, dithianes, THF, dioxane, acetonitrile, dichloromethane, dichloroethane, diethyl ether, pyridine, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide, or any combination thereof, though preferably neat.
- this conversion is accomplished by combining the protected glycoside in a non polar, aprotic solvent such as ether or pet ether.
- the glycal can be formed at any temperature that is suitable for the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products, preferably temperatures below room temperature, such as 10 °C.
- the product crystallizes as it forms.
- the crystalline halo- sugar is then filtered, washed with solvent, such as pet ether, and dried to provide the halo sugar in storable form.
- the coupling reaction forms a carbon-nitrogen bond between the 1 -carbon of the 1 -halo-sugar, such as a l-halo-2-deoxy ribose, and a ring nitrogen of a pyrimidine, purine, heterocyclic or heteroaromatic base.
- the carbonyls and amine groups, if any, of the base can be optionally protected with any suitable protecting group known in the art.
- Useful protecting groups for the carbonyl group of, for example, uracil, thymine include trimethyl silyl and triethylsilyl, t- butydimethysilyl, methyl, and other alkyl ethers.
- Useful protecting groups for the amine group of adenine and guanine include the trityl group, the tosylate, acyl groups such as acetyl, benzoyl, and alkoxycarbonyl groups, such as benzoyl oxy carbonal, t-butoxycarbonal, and fluroenylmethylcarbonyl.
- the halo-sugar can be coupled to the pyrimidine, purine, heterocyclic or heteroaromatic base using any means known in the art, to obtain an optionally protected nucleoside.
- an activated purine or pyrimidine base preferably a silylated base
- a Lewis acid such as tin tetrachloride, titanium tetrachloride, or trimethylsilyl triflate.
- the base can be first combined with a silylating agent such as hexamethyldisilazane, to activate the base, for example, in the case or uracil or thymine, to silylated the amide carbonyls.
- a silylating agent such as hexamethyldisilazane
- the resulting activated base can then be combined with the optionally protected halo sugar described above to form the protected nucleoside.
- Figure 3 One non-limiting example of such coupling is illustrated in Figure 3.
- the pyrimidine, purine, heterocyclic or heteroaromatic base such as uracil or thymine
- a stochiometric excess of silylating agent such as hexamethyldisilazane
- a mild acidic catalyst such as ammonium sulfate
- the silylated derivative is combined with the halo-sugar under solvated conditions without prior isolation to form the nucleoside.
- the optionally protected nucleoside can then be deprotected if necessary by any means known in the art.
- treatment of the protected nucleoside with mild base can remove the ditoluoyl groups and yield the deprotected nucleoside.
- the key starting material for this process is an appropriately substituted arylsulfonic acid and pyridinium analog.
- the arylsulfonic acid and pyridinium base analog can be purchased or can be prepared by any known means including standard nucleophilic and electrophilic aromatic substitution.
- the arylsulfonic acid and pyridinium base can equilibrate to form the title compounds preferably without further catalysis.
- the proton exchange reaction can be carried out at any temperature that achieves the desired results, i.e., that is suitable for the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products.
- Preferred temperatures are from room temperature to 75°C.
- Any reaction solvent can be selected that can achieve the necessary temperature and that can solubilize the reaction components, though preferably not the desired salt product.
- Non-limiting examples are any aprotic solvent including, but not limiting to, alkyl or halo-alkyl solvents such as hexane, cyclohexane, dichloromethane or dichloroethane, toluene, acetone, ethyl acetate, difhianes, THF, dioxane, acetonitrile, diethyl ether, pyridine, dimethylformamide (DMF), dimefhylsulfoxide (DMSO), dimethylacetamide, or any combination thereof.
- the preferred solvent system is anhydrous dichloromethane followed by cyclohexane to promote in situ precipitation of the salt product. 4.
- the key starting material for this process is an appropriately substituted uridine nucleoside, such as a ⁇ -L-2'-deoxyuridine.
- the appropriately substituted uridine nucleoside, such as ⁇ -L-2'-deoxyuridine, can be purchased or can be prepared by any known means including the procedures disclosed herein.
- the amination of the appropriately protected/substituted uridine nucleoside, such as an optionally protected ⁇ - L-2'-deoxyuridine, is accomplished with a sulfonyl halide, such as a tosyl halide, and in particular a tosyl chloride, optionally in the presence of a phase transfer catalyst such as a pyridinium arylsulfonate disclosed above, followed by treatment with ammonia (gaseous or liquid), affords the title compound.
- a phase transfer catalyst such as a pyridinium arylsulfonate disclosed above
- the amination reaction can be carried out at any temperature that achieves the desired results, i.e., that is suitable for the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products, preferably room temperature.
- Any reaction solvent can be selected that can achieve the necessary temperature and that can solubilize the reaction components.
- Non-limiting examples are any aprotic solvent including, but not limiting to, alkyl or halo-alkyl solvents such as hexane, cyclohexane, dichloromethane (DCM) or dichloroethane, toluene, acetone, ethyl acetate, di hianes, THF, dioxane, acetonitrile, diethyl ether, pyridine, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide, or any combination thereof, preferably dichloromethane.
- alkyl or halo-alkyl solvents such as hexane, cyclohexane, dichloromethane (DCM) or dichloroethane, toluene, acetone, ethyl acetate, di hianes, THF
- the optionally protected cytidine nucleoside such as an N-protected amino acid based prodrugs
- the optionally protected cytidine nucleoside can be deprotected by methods well known to those skilled in the art, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.
- the N-Boc protected amino acids can be deprotected with HCl in ethyl acetate at room temperature.
- One embodiment of the invention is directed to the process described in Figure 4, which results in improved productivity and efficiency of each step carried out with added safety and technical convenience and resulting in elevated product purities in each step.
- a preferred embodiment begins with a starting uracil nucleoside optionally protected in the 5 '-position of the sugar moiety, for example with a trityl derivative.
- the purified 5'-O-protected-uracil nucleoside can optionally be protected, for example aminoacylated, at the 3 '-position by direct incorporation of the desired protecting group, such as an amino acyl group.
- This 3 '-protected intermediate for example the aminoacylated intermediate, optionally can be selectively deprotected at the 5 '-position of the sugar moiety.
- a 3 '-protected intermediate that is tritylated at the 5'- position can be detritylated under mild acidic conditions, and the 3 '-protected intermediate, such as an aminoacyl-uracil nucleoside, is converted to a 3 '-aminoacylated cytosinylnucleoside.
- the 5 '-position of a uridine nucleoside is tritylated, followed by aminoacylation at the 3 '-position, selectively deprotected at the 5 '-position, and aminated to give a 3 '-aminoacylated cytidine nucleoside.
- the conversion involves the following sequential steps: 1) O-Boc-protection of the 5'-position of a 3 '-aminoacylated uridine nucleoside, 2) tosylation of the uracil moiety, 3) amination of the tosylated uracil moiety to form the cytosinyl moiety, and 4) removal of the Boc-protective groups to form a 3'-aminoacyl-cytosine nucleoside.
- the foregoing steps for transformation of uracil derivatives to cytosine derivatives provide a significant improvement for multi-kilogram production of high purity the cytidine derivatives for pharmaceutical use.
- the combination of the individual steps provides the additional advantage of minimizing waste and maximizing the efficiency of the industrial plant.
- the use of O-Boc protection for the 5'- hydroxyl group minimizes the number of steps and impurities in the final product. This use is especially applicable when a 3'-Boc-aminoacyl is the substituent R .
- a single deprotection step affords the desired prodrug.
- the selective extraction step to separate the uracil derivative from the desired cytosine derivative also conveys advantages as described above.
- the 2 '-deoxy cytidine nucleosides are prepared using the following steps.
- the tritylation step combines the deoxyribonucleoside (2, Figure 3), with a tritylating agent, acid scavenger and catalyst in organic solvent. This tritylation step adds a protecting group to the 5 '-hydroxyl group of the 2-deoxyribose moiety but not to
- the tritylating agent may be a trityl or substituted trityl halide wherein the substituent may be a mono, di or tri alkyl of 1 to 3 carbons or a mono, di or tri halo group.
- the acid scavenger may be an organic base such as triethyl amine or pyridine.
- the preferred catalyst is dimethylaminopyridine (DMAP).
- DMAP dimethylaminopyridine
- Solvents for the reaction are chlorinated hydrocarbons, esters, and ethers, preferably dichloromethane or ethyl acetate, in amounts varying from 5 to 30 parts by volume per one part by weight of the starting nucleoside, more preferably 8, 9, 10 or 11 parts.
- the preferred acid scavenger is pyridine, the minimum required amount is 1 part of the starting nucleoside to promote partial solubilization of the nucleoside.
- the preferred catalyst is DMAP, in amounts varying from 1 to 10 mol%, more preferably 5 mol% per mole of the starting nucleoside.
- tritylating agents are trityl chloride and substituted trityl chlorides, used in amounts varying from 1 to 1.3 moles, more preferably 1.1 moles per mole of the starting nucleoside.
- the tritylation reaction is preferably conducted at a temperature ranging from about 10 °C to about 40 °C, more preferably from 30 °C to 35 °C.
- the reaction mixture can be purified by any convenient technique known to separate polar materials from nonpolar materials.
- pyridine and other polar impurities can be removed from the nucleoside containing solution by aqueous liquid- liquid extractions.
- Preferred purification is performed by aqueous liquid-liquid extraction using sequential extraction of the organic reaction mixture with aqueous acid solution until substantially complete removal of pyridine, followed by extraction with aqueous sodium bicarbonate solution and water, to adjust the pH of the solution containing the protected nucleoside to 5-6;
- the product can be crystallized from a mixture of organic solvents capable of retaining the non-polar impurities.
- organic solvents are chlorinated hydrocarbons and ketones, preferably dichloromethane and methyl isobutyl ketone
- MIBK MIBK
- the sequential acylation and detritylation steps involve acylation of the 3' hydroxyl group of the 2-deoxyribose moiety and removal of the protecting group from the 5' hydroxyl.
- the acyl group may be derived from any pharmaceutically acceptable carboxylic acid, any naturally occurring alpha-amino acid or any non-natural pharmaceutically acceptable amino acid as described above.
- the acyl group (including the aminoacyl group) provides a prodrug character to the final product.
- the acylation may be conducted according to any esterification technique for esterifying an acid or amino acid with an alcohol. In the case of an amino acid, its amino group will be protected with BOC.
- a preferred example of this step involves reacting a mixture of a 5'-trityl- deoxyribonucleoside and a carboxylic acid in a dry organic solvent, in the presence of a catalyst, with a solution of the carbodiimide in the same organic solvent at low temperatures (10-1 °C).
- the carboxylic acid is an N-protected amino acid, preferably Boc- -valine, in amounts varying from 1 to 1.3 moles of the starting nucleoside, preferably 1.1 moles.
- Preferred solvents for the reaction are chlorinated hydrocarbons, esters or ethers, preferably dichloromethane and/or ethyl acetate, in amounts varying from 5 to 15 parts by volume per one part by weight of the starting nucleoside, more preferably 6, 7, or 8 parts.
- Preferred catalysts are substituted pyridines, preferably DMAP, in amounts varying from 1 to 10 mol%, more preferably up to 5 mol% per mole of the starting nucleoside.
- Preferred carbodiimide is DCC in amounts varying from 1 to 1.5 moles of the starting nucleoside, preferably 1.2 moles.
- the acylated intermediate is separated from the reaction mixture by filtering the neutral urea by-product and extracting the nucleoside containing solution to remove the polar impurities.
- Preferred purification is performed by aqueous liquid-liquid extraction using sequential extraction of the organic reaction mixture with aqueous acid solution to remove DMAP, followed by extraction with aqueous sodium bicarbonate solution to adjust the pH of the organic phase to 5-6 and finally with brine. Additional filtration to remove DCU may be necessary; following partial distillation of the reaction solvent.
- Detritylation is accomplished by acid catalyzed thiol exchange.
- the partially distilled solution of the aminoacylated trityl-nucleoside is reacted with a thiol in the presence of an acid catalyst at temperatures in the range of 20 to 40 °C, preferably 28-32 °C.
- Preferred thiols are mercaptoethanol and ethanethiol in amounts varying from 1 to 1.3 moles per mole of the starting nucleoside, preferably 1.1 moles.
- a preferred catalyst is p-toluenesulfonic acid, in amounts varying from 1 to 10 mol%, more preferably 7-8 mol% per mole of the starting nucleoside.
- the reaction is quenched with an amine, preferably triethylamine in amounts varying from 1 to 10 mol%, more preferably 7-8 mol% per mole of the starting nucleoside.
- the reaction mixture is extracted with brine to remove the amine salt.
- the acylated intermediate is crystallized from a mixture of organic solvents capable of retaining majority of the non-polar impurities after distilling the reaction solvent.
- Preferred organic solvents are hydrocarbons and aromatic hydrocarbons, preferably xylene and hexanes in the ratio of 1:1, in amounts varying from 2 to 4 parts by volume per one part by weight of the starting nucleoside.
- the non-polar impurities are removed by treating the product several times (typically 3 to 5 times) with the same solvent mixture used above until the non-polar impurities are removed from the protected nucleoside. Boc-protection-tosylation-amination-deprotection steps.
- the present invention is based at least in part upon the discovery that carrying out a sequential Boc protection of the 5' hydroxyl, tosylation at C-4 in the uracil moiety and its conversion to an amino group can be carried out without isolation of intermediates, or in other words, can be carried out in an uninterrupted fashion.
- the Boc-protected uracylnucleoside is to be used as soon as the reaction is complete.
- the reaction can be followed by any convenient identification technique such as high performance liquid chromatography (HPLC), thin layer chromatography (TLC) and the like to determine reaction end point. Immediately following the end point, the reactants of the tosylation reaction are incorporated into the reaction mixture.
- the Boc protected intermediate is not allowed to stand in a completed form for longer than 3, more preferably 1 hour.
- the potassium carbonate base is in the sesquihydrate form and is to be freshly prepared so that the tosylation reaction will be rapidly completed upon the addition of the tosylating agent. It has been found that, especially for multi-kilogram preparations, use of stale potassium carbonate sesquihydrate produces a very slow reaction, results in decomposition of the reactive intermediates and necessitates additional incorporation of reagents. It was discovered that the sesquihydrate form of potassium carbonate allows the tosylation reaction to proceed at low temperatures, which is desirable especially in the presence of aminoacyl groups to avoid racemization.
- the reaction mixture Upon completion of the tosylation reaction, the reaction mixture is filtered under inert atmosphere and low vacuum to minimize exposure to humidity.
- the use of a solution of liquid ammonia in dichloromethane for the amination reaction is also an important feature of this invention since it allows the addition of a more precise amount of animating agent.
- the tosylating agent is tosyl chloride
- the ratio of cytidine to uridine at the end of amination is in the range of 12-15 to 1.
- the selective extraction employed in this invention to remove the uridine byproducts represents an important achievement for the large scale preparation of cytidine nucleosides starting from uridine derivatives, since this was previously accomplished only by column chromatography.
- selective extraction efficiently removes uridine derivatives from the reaction solution.
- the deprotection step can be carried out having a maximum of 2% or uridine derivative as contaminant in the solution, without compromising the purity of the final product.
- the 2'-deoxycytidine nucleosides are prepared using the following steps.
- a 3'-acyl-deoxyribonucleoside is reacted with a solution of BOC-anhydride in a dry organic solvent, in the presence of a catalyst at controlled temperatures (23-26°C).
- Preferred solvents for the reaction are chlorinated hydrocarbons, esters or ethers, preferably dichloromethane and/or ethyl acetate, in amounts varying from 5 to 15 parts by volume per one part by weight of the starting nucleoside, more preferably 6, 7, or 8 parts.
- Preferred catalysts are substituted pyridines, preferably DMAP, in amounts varying from 1 to 10 mol%, more preferably 5 mol% per mole of the starting nucleoside.
- reaction solution of a) is reacted with a sulfonate such as p-toluenesulfonyl chloride in the presence of potassium carbonate sesquihydrate and DMAP-tosylate at 25-27 °C.
- a sulfonate such as p-toluenesulfonyl chloride
- potassium carbonate sesquihydrate and DMAP-tosylate 25-27 °C.
- the salts are filtered and the reaction solution is diluted with dichloromethane followed by reaction with ammonia at 18-22 °C.
- the cytidine derivative is purified by selective extraction of the uridine derivative with mixture of organic solvents upon conversion of the cytidine derivative to its hydrochloric salt.
- Preferred combination of polar solvents is water and methanol within the range of about 1:1 to about 5:1, by volume, more preferably a gradient proportion from 1.5:1 to 3:1.
- Preferred combination of non-polar solvents is hexanes and ethyl acetate within the range of about 4:1 to 2:1, by volume, more preferably a gradient proportion from 3 : 1 to 2: 1.
- the key starting material for this process is an appropriately substituted 2'- deoxy- ⁇ -D or ⁇ -L nucleoside.
- the 2'-deoxy- ⁇ -D or ⁇ -L nucleoside can be purchased or can be prepared by any known means including standard coupling reactions with D or L deoxyribose.
- the title compounds then can be made by selectively coupling an amino acid to 2'-deoxy- ⁇ -L-nucleosides without any protection of the nucleoside.
- the coupling reaction can be achieved using appropriate coupling reagents that promote the coupling.
- suitable coupling reagents include Mitsunobu- type reagents (e.g. dialkyl azodicarboxylates such as diisopropyl azodicarboxylate and diethyl azodicarboxylate) with triphenyl phosphine or various types of carbodiimides.
- the coupling reaction can be carried out at any temperature that achieves the desired results, i.e., that is suitable for the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products.
- Any reaction solvent can be selected that can achieve the necessary temperature and that can solubilize the reaction components.
- Non-limiting examples are any aprotic solvent including, but not limiting to, alkyl or halo-alkyl solvents such as hexane, cyclohexane, dichloromethane or dichloroethane, toluene, acetone, ethyl acetate, dithianes, THF, dioxane, acetonitrile, diethyl ether, pyridine, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide, or any combination thereof.
- Method for the preparation of 3'- ⁇ ?-aminoacyl derivatives of 2'-deoxy- ⁇ -L- nucleosides such as hexane, cyclohexane, dichloromethane or dichloroethane, toluene, acetone, ethyl acetate, dithianes
- the key starting material for this process is also an appropriately substituted 2'- deoxy- ⁇ -D or ⁇ -L nucleoside.
- the 2' -deoxy- ⁇ -D or ⁇ -L nucleoside can be purchased or can be prepared by any known means including standard coupling reactions with D or L deoxyribose.
- the title compounds can be made by first selectively protecting the 5 '-hydroxyl with a suitable oxygen protecting group, such as an acyl or silyl protecting group, and optionally protecting any free amino in the heterocyclic or heteroaromatic base.
- a suitable oxygen protecting group such as an acyl or silyl protecting group
- the free 3 '-hydroxyl can be coupled to a N-protected or ⁇ amino acid.
- the coupling reaction can be achieved using appropriate coupling reagents that promote the coupling.
- suitable coupling reagents include Mitsunobu- type reagents (e.g. dialkyl azodicarboxylates such as diisopropyl azodicarboxylate and diethyl azodicarboxylate) with triphenyl phosphine or various types of carbodiimides.
- the coupling reaction can be carried out at any temperature that achieves the desired results, i.e., that is suitable for the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products.
- Any reaction solvent can be selected that can achieve the necessary temperature and that can solubilize the reaction components.
- ⁇ on-limiting examples are any aprotic solvent including, but not limiting to, alkyl or halo-alkyl solvents such as hexane, cyclohexane, dichloromethane or dichloroethane, toluene, acetone, ethyl acetate, dithianes, THF, dioxane, acetonitrile, diethyl ether, pyridine, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide, or any combination thereof. 7.
- the key starting material for this process is also an appropriately substituted 2'- deoxy- ⁇ -D or ⁇ -L nucleoside.
- the 2'-deoxy- ⁇ -D or ⁇ -L nucleoside can be purchased or can be prepared by any known means including standard coupling reactions with D or L deoxyribose.
- the protection can be carried out at any temperature that achieves the desired results, i.e., that is suitable for the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products.
- Any reaction solvent can be selected that can achieve the necessary temperature and that can solubilize the reaction components.
- Non-limiting examples are any aprotic solvent including, but not limiting to, alkyl or halo-alkyl solvents such as hexane, cyclohexane, dichloromethane or dichloroefhane, toluene, acetone, ethyl acetate, dithianes, THF, dioxane, acetonitrile, diethyl ether, pyridine, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide, or any combination thereof.
- alkyl or halo-alkyl solvents such as hexane, cyclohexane, dichloromethane or dichloroefhane, toluene, acetone, ethyl acetate, dithianes, THF, dioxane, acetonitrile, dieth
- the free 3 '-hydroxyl can be coupled to a N-protected ⁇ or ⁇ amino acid.
- the coupling reaction can be achieved using appropriate coupling reagents that promote the coupling.
- Some non-limiting examples of coupling reagents are Mitsunobu- type reagents (e.g. dialkyl azodicarboxylates such as diisopropyl azodicarboxylate and diethyl azodicarboxylate) with triphenyl phosphine or various types of carbodiimides.
- the coupling reaction can be carried out at any temperature that achieves the desired results, i.e., that is suitable for the reaction to proceed at an acceptable rate without promoting decomposition or excessive side products.
- Any reaction solvent can be selected that can achieve the necessary temperature and that can solubilize the reaction components.
- aprotic solvent including, but not limiting to, alkyl or halo-alkyl solvents such as hexane, cyclohexane, dichloromethane or dichloroethane, toluene, acetone, ethyl acetate, dithianes, THF, dioxane, acetonitrile, diethyl ether, pyridine, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide, or any combination thereof.
- alkyl or halo-alkyl solvents such as hexane, cyclohexane, dichloromethane or dichloroethane, toluene, acetone, ethyl acetate, dithianes, THF, dioxane, acetonitrile, diethyl ether, pyridine
- the starting materials include 2-deoxy-L-ribose, 27 Kg; methyl alcohol, 189 Lt; methanesulfonic acid, 0.27 Lt; dimethylaminopyridine, 2.46 Kg; toluene, 55 Lt.; ethyl acetate, 28 Lt.
- methyl glycoside formation To conduct the methyl glycoside formation, methanol, 162 Lt, is charged into the reactor with stirring. Then the starting sugar, L-2-deoxyribose, 27 Kg, is dissolved in the methanol and the temperature maintained at 25-30C. Next the acid catalyst methanesulfonic acid, MSA, 0.27 Lt, is dissolved in methanol, 27 Lt, and added.
- MSA methanesulfonic acid
- reaction is followed by thin layer chromatography to confirm complete transformation (usually 15-30minutes) (tic DCM/MeOH, 9:1).
- the acid catalyst is then quenched by addition of dimethylamino pyridine, DMAP, 2.46 Kg.
- the reaction medium is stirred for about 30 minutes at which time the pH is confirmed to be about 9.
- the methanol is distilled under vacuum taking care to hold the temperature below
- the reagents include ethyl acetate, 108 Lt.; toluoyl chloride, 55.8 Lt.; triethylamine, 66 Lt.
- the protected methyl glycoside is produced by acylating the methyl glycoside of Example 1
- step 1 The product from step 1 is dissolved in ethyl acetate, 54 Lt, and under argon, the contents are stirred and cooled to 3-5°C. Triethyl amine, TEA, 6 Lt, is added and cooling liquid is circulated at 3-5°C. Toluoyl chloride, 55.8 Lt, in ethyl acetate, 54 Lt, is then pumped into the above mixture at a rate such that the temperature of the reaction mixture does not rise above 15-17°C. This condition is maintained for the first 50% of the addition. After that, the cooling system is stopped and the addition continued allowing the reaction to achieve 32-35°C.
- the resulting mixture is washed (stirred for 30 minutes) with an aqueous, 54 Lt, solution of sulfuric acid, 5.4 Lt, containing acetic acid, 0.54 Lt.
- the aqueous phase is extracted twice with methylene chloride, DCM (2 x 11 Lt) and the DCM extracts mixed with the main organic phase.
- the organic phase is washed with brine (2 x 34 Lt), and about 50% of the solvent is then distilled and the concentrate (107.3 Kg) is preserved for the next step.
- the reagents include the product from step 2, equivalent to 7.5 Kg of 2-deoxy-L- ribose; acetyl chloride, 30 Lt.; petroleum ether, 36 Lt.; methyl alcohol, 6 Lt.
- the chloro sugar is produced by exposing the product of Example 2 to a collateral substitution reaction.
- a glass-lined reactor is charged with the ethyl acetate solution from step 2 containing the equivalent of 7.5 Kg of 2-deoxy-L- ribose.
- the ethyl acetate is removed by vacuum distillation (temperature in the jacket is 50°C). The temperature of the mixture is lowered to 25°C and the vacuum broken letting Argon into the reactor.
- acetyl chloride is charged to the reactor, 30 Lt, followed by pet. ether, 30 Lt.
- the mixture is stirred under argon and the temperature of the solution lowered to 8-10°C.
- Methanol, 6 Lt, in pet. ether, 6 Lt is then pumped in the reactor keeping the temperature between 8-10°C.
- Total time of addition is approximately 3.5-4 hours.
- massive precipitation is observed along with a raise in temperature to about 15-16°C.
- the temperature is allowed to go down to 8-10°C and the addition of methanol continued.
- the reaction mixture is then stirred for 4 additional hours at 8-10°C.
- the reaction mixture contains a precipitate of the chloro sugar suspended in the organic solvent.
- the product is filtered in a glass filter under an argon atmosphere.
- the product is washed twice with pet. ether, 5 Lt.
- the cake is then suspended in pet. ether, 80 Lt, and stirred at 25°C under argon for 10 minutes.
- the product is re-filtered and the cake is washed as before.
- the vacuum is replaced by a current of argon that flows through the cake leading to complete elimination of solvents.
- the dried cake is then transferred to double polyethylene bags under argon and stored at 15°C. Yield is 17.7 Kg.
- reaction materials for this coupling reaction are as follows. Thymine, 41.8 Kg; ammonium sulfate 0.67 Kg; hexamethyldisilazane, 75 Lt; toluene, 42 Lt; chorosugar, 83.53 Kg; chloroform, 919 Lt; ethyl alcohol, 869 Lt
- the reactor is flushed with N 2 (g) for 10 minutes.
- Thymine (41.8 Kg), ammonium sulfate (0.67 Kg), 1,1, 1,3 ,3 ,3 -hexamethyldisilazane) (75 Lt), and toluene (42 Lt) are charged to the reactor.
- the reaction mixture is stirred and heated for 5-8 hours to a gentle reflux (jacket temp to 130°C) (dissolution should have occurred).
- the reaction mixture is then cooled to 60°C and the solvent is vacuum distilled while heating to 130°C (this step removes excess 1,1,1,3,3,3-hexamethyldisilazane and toluene).
- Toluene (42 Lt) is charged and vacuum distilling continued, jacketed to 145°C. Reactor can be flushed with N 2 while vacuum distilling at 100°C to drive off last traces if HMDS. Ideally this step produces a viscous, stirrable reaction mixture with a white layer on top, a sign that all HMDS has been eliminated. Gas chromatography can be used to ensure that all HMDS is eliminated.
- the reaction mixture is stirred for 1 more hour at 22°C (+/-2°C). Then, celite (ca 41.86 Kg) is added, the slurry is cooled to 15°C (+/-2°C) and ethanol (48 L) is slowly charged. The slurry is stirred for 30 minutes, then sodium bicarbonate (52 Kg) is added as a saturated aqueous solution (in ca 57 Lt water). The pH of the solution should be between 5-7.
- reaction mixture is filtered through a celite pad and the filter cake is washed 2 X 42 Lt of chloroform. The filtrate (clear) and washings and combined. Then water (90 Lt) is charged to filtrate. The contents are stirred for 30min, agitation stopped and the contents allowed to settle for lOmin. HPLC is performed to assay disappearance of Thymine.
- the contents are transferred for separation and bottom organic layer retained.
- the top aqueous layer is discarded as waste.
- the organic layer is recharged to the reactor.
- Water (90 Lt) is charged to the reactor and the contents stirred for 30min, agitation stopped and the contents allowed to settle for lOmin.
- the contents can be distilled under vacuum at ca. 60°C.
- the bottom organic layer is retained and the top aqueous layer discarded.
- Ethanol (678 Lt.) is charged to reaction mixture and stirred at 60°C for 1 hour.
- the reaction mixture is cooled to 20°C and stirred for 1 hour at this temperature.
- the reaction mixture is filtered and wash through with 95% ethanol (3 X 16 Lt).
- the solid is dried in a vacuum oven at 60°C/ 800mbar to constant weight.
- reaction mixture was diluted with ethanol (15 L) and stirred for 30 minutes.
- the chloroform was distilled and the product crystallized from the reaction mixture.
- the cake was filtered, washed with ethanol and dried in vacuum at 60-65 °C.
- a 100-gallon glass-lined reactor under argon was charged with 113 liters of dichloromethane, 11 liters of dry pyridine, 0.305 Kg of DMAP, 11.3 Kg of dry, milled 2'-deoxy-Z-uridine, and 15.3 Kg of trityl chloride, and the mixture was heated to 30- 34 °C with vigorous stirring for 12-16 hours. The heterogeneous mixture progressively became homogeneous. The progression of the reaction was monitored by TLC. Upon completion, the reaction was quenched with 900 mL of methanol and cooled to 24-28 °C.
- the mixture was extracted twice with 38 L aqueous sulfuric acid solution (6.9 Kg cone sulfuric acid in 70 L of water) and once with 10% aqueous sodium bicarbonate (30 L). The mixture was then extract with water (30 L) until pH 5-6. The reactor jacket was then heated to 65 °C and 85% of the dichloromethane was distilled off. The concentrated mixture was cooled to 25-30 °C and diluted with 12 L of methyl isobutyl ketone under moderate stirring. The mixture was chilled to 8-10 °C for 2 hours. The crystalline mass was filtered and the solid was washed with cold dichloromethane (2-5 L), then dried in vacuo at 50 °C to constant weight to yield 19.18 Kg (81.6%) of 5 '-Trityl-L-dU.
- a 100-gallon glass-lined reactor under argon was charged with 133 liters of dichloromethane, 0.247 Kg of DMAP, 9.65 Kg of N-Boc-I-valine, and 19.0 Kg of dry, finely ground 5'-O-trityl-2'-deoxy---.-uridine, and the mixture was cooled to 10-14°C with stirring.
- reaction Upon completion (2 to 3 hours), the reaction was filtered through filtering aid, and the solution extracted with aqueous sulfuric acid solution (1.37 L of concentrated sulfuric acid in 27.2 L of water), 10% aqueous sodium bicarbonate (27.2 L) until pH 5-6, and brine (30 L). The reactor jacket was then heated to 65°C and 85% of the dichloromethane was distilled off. This concentrated solution can be used as such for the next step or the product can be seed to crystallize.
- Example 9 The concentrated solution obtained in Example 9 was cooled to 20-30°C and the mercaptoethanol (3.12 L) and p-toluenesulfonic acid (0.57 Kg) were added under vigorous stirring. The reaction mixture was heated to 28-32°C until TLC showed completion of the reaction (ca. 5 h). Then triethylamine (0.436 L) was added and the solution stirred for 30 min. The solution was extracted with 54 L of brine and the organic phase concentrated to a syrup. Xylene (51 L) was added to the concentrate and distillation of residual dichloromethane continued. Hexanes (51 L) was added and the suspension stirred for 30 min.
- the reaction solution was heated to 28-30°C and extracted twice with water and aqueous sulfuric acid until pH 6.5-7.0.
- the dichloromethane was distilled to ! of the volume and the reaction solution was diluted with methanol (27 L). Distillation was continued until complete removal of dichloromethane.
- the reaction solution was cooled to 10 - 15°C, acidified to pH 2 with diluted aqueous HCl solution and diluted with water (27 L). Water (19 Kg) was added, followed by ethyl acetate (9 Kg). The mixture was allowed to stir for 10 minutes at 10 °C.
- the hydrogen chloride solution was pumped into the reaction solution of Example 13, within 40 minutes, under argon.
- the reaction mixture was stirred overnight at 33-35°C when TLC using ethyl acetate / methanol (3:1) showed that the reaction was complete.
- the reaction solution was cooled to 25-27°C and ethyl acetate
- the filtercake (NHU + TsO) was rinsed with CH 2 C1 2 and then air dried; it amounted to 24.87g (82%). The filtrate was then concentrated by evaporation to remove the excess NH 3 . The filtered reaction solution was extracted with 0.1M HCl (4 x lOOmL) to remove excess DMAP and water. It was found that EtOAc is optimal solvent to put the material on the column.
- the sample is stored in an inert atmosphere, such as under argon or nitrogen.
- the solvents are degasified before use.
- the sample is injected immediately after preparation.
- the sample is stored in an inert atmosphere, such as under argon or nitrogen.
- the solvents are degasified before use.
- the sample is injected immediately after preparation.
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EP04722357A Withdrawn EP1745573A4 (de) | 2003-03-20 | 2004-03-22 | Verfahren zur herstellung von 2 -deoxy-beta-l-nukleosiden |
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EP (1) | EP1745573A4 (de) |
KR (1) | KR20060008297A (de) |
CN (1) | CN101415719A (de) |
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WO (1) | WO2004084453A2 (de) |
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EA007867B1 (ru) | 2000-05-26 | 2007-02-27 | Айденикс (Кайман) Лимитед | Композиции для лечения флавивирусных и пестивирусных инфекций и способы их применения |
US7608600B2 (en) | 2002-06-28 | 2009-10-27 | Idenix Pharmaceuticals, Inc. | Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections |
AP2005003213A0 (en) | 2002-06-28 | 2005-03-31 | Univ Cagliari | 2'-C-methyl-3'-O-L-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections. |
US7824851B2 (en) | 2002-11-15 | 2010-11-02 | Idenix Pharmaceuticals, Inc. | 2′-branched nucleosides and Flaviviridae mutation |
CN1812995A (zh) * | 2003-04-28 | 2006-08-02 | 艾登尼科斯(开曼)有限公司 | 工业化规模的核苷合成 |
EP2345659A1 (de) | 2003-05-30 | 2011-07-20 | Pharmasset, Inc. | Modifizierte fluorinierte Nukleosidanaloga |
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EP1809301B1 (de) | 2004-09-14 | 2019-11-06 | Gilead Pharmasset LLC | 2-fluoro-2-alkyl-substituierte d-ribonolacton-zwischenprodukte |
CA2634749C (en) | 2005-12-23 | 2014-08-19 | Idenix Pharmaceuticals, Inc. | Process for preparing a synthetic intermediate for preparation of branched nucleosides |
GB0609178D0 (en) | 2006-05-09 | 2006-06-21 | Univ Cardiff | Novel compounds |
US7964580B2 (en) | 2007-03-30 | 2011-06-21 | Pharmasset, Inc. | Nucleoside phosphoramidate prodrugs |
US8173621B2 (en) | 2008-06-11 | 2012-05-08 | Gilead Pharmasset Llc | Nucleoside cyclicphosphates |
US8586729B2 (en) * | 2008-10-03 | 2013-11-19 | Scinopharm Taiwan Ltd. | Synthesis of decitabine |
EP2341772B1 (de) * | 2008-10-03 | 2013-04-17 | ScinoPharm Taiwan, Ltd. | Decitabinsynthese |
US8716262B2 (en) | 2008-12-23 | 2014-05-06 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
US8551973B2 (en) | 2008-12-23 | 2013-10-08 | Gilead Pharmasset Llc | Nucleoside analogs |
SG194404A1 (en) | 2008-12-23 | 2013-11-29 | Gilead Pharmasset Llc | Synthesis of purine nucleosides |
TWI576352B (zh) | 2009-05-20 | 2017-04-01 | 基利法瑪席特有限責任公司 | 核苷磷醯胺 |
US8618076B2 (en) | 2009-05-20 | 2013-12-31 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
CN104017020B (zh) | 2010-03-31 | 2017-04-12 | 吉利德制药有限责任公司 | 核苷氨基磷酸酯 |
PL3290428T3 (pl) | 2010-03-31 | 2022-02-07 | Gilead Pharmasset Llc | Tabletka zawierająca krystaliczny (S)-2-(((S)-(((2R,3R,4R,5R)-5-(2,4-diokso-3,4-dihydropirymidyn-1(2H)-ylo)-4-fluoro-3-hydroksy-4-metylotetrahydrofuran-2-ylo)metoksy)(fenoksy)fosforylo)amino)propanian izopropylu |
KR101241321B1 (ko) * | 2010-08-05 | 2013-03-11 | 케이피엑스 라이프사이언스 주식회사 | 수율 및 순도가 개선된 데시타빈의 제조방법 |
WO2012075140A1 (en) | 2010-11-30 | 2012-06-07 | Pharmasset, Inc. | Compounds |
US8889159B2 (en) | 2011-11-29 | 2014-11-18 | Gilead Pharmasset Llc | Compositions and methods for treating hepatitis C virus |
NZ716840A (en) | 2013-08-27 | 2017-06-30 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
CN104744538A (zh) * | 2013-12-26 | 2015-07-01 | 康普药业股份有限公司 | 一种替比夫定的制备方法 |
CN104059057A (zh) * | 2014-01-03 | 2014-09-24 | 石家庄龙泽制药有限公司 | 拉米夫定杂质3-tu的制备方法 |
CN104356186B (zh) * | 2014-10-24 | 2017-03-15 | 济南尚博生物科技有限公司 | 一种3’,5’‑二‑氧‑(4‑对甲基苯甲酰基)‑β‑L‑胸腺嘧啶的制备方法 |
CN106478752B (zh) * | 2015-09-01 | 2019-10-25 | 四川科伦药物研究院有限公司 | 一种替比夫定的制备方法 |
JP6743135B2 (ja) * | 2015-09-02 | 2020-08-19 | アッヴィ・インコーポレイテッド | 抗ウィルス性テトラヒドロフラン誘導体 |
CN108299518A (zh) * | 2018-02-02 | 2018-07-20 | 王成宇 | 一种2`-脱氧-β-尿苷的合成方法 |
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- 2004-03-22 EP EP04722357A patent/EP1745573A4/de not_active Withdrawn
- 2004-03-22 US US10/806,296 patent/US7582748B2/en active Active
- 2004-03-22 KR KR1020057017617A patent/KR20060008297A/ko not_active Application Discontinuation
- 2004-03-22 WO PCT/IB2004/001308 patent/WO2004084453A2/en active Application Filing
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Also Published As
Publication number | Publication date |
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WO2004084453A3 (en) | 2009-04-02 |
KR20060008297A (ko) | 2006-01-26 |
US7582748B2 (en) | 2009-09-01 |
EP1745573A4 (de) | 2010-05-26 |
US20040266996A1 (en) | 2004-12-30 |
BRPI0408561A (pt) | 2006-03-21 |
CN101415719A (zh) | 2009-04-22 |
WO2004084453A2 (en) | 2004-09-30 |
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